The musculoskeletal system is vital to almost everything that we as humans do in our daily lives. Joint health is pivotal to our mobility, and to our interactions with the world. Unfortunately for many of us, our joints fail as we age or in response to injury. Movement becomes painful and simple tasks become onerous. Osteoarthritis (OA), the progressive degeneration of joint tissues including the articular cartilage lining joints, represents an enormous economic and societal burden and is a leading cause of disability worldwide. There are no disease modifying treatments for OA, and despite advances in cartilage repair, no treatment is truly regenerative. Moreover, due to the poor performance of repair procedures in all but the most pristine joints (which are clinically atypical) most patients are excluded from benefiting from such advances. The first half of this thesis seeks to understand the initiation, progression, and treatment of OA, both generally and in an understudied context (the human thumb joint) and offers a proof-of-concept framework for biologic joint resurfacing. The second portion of the thesis focuses on the knee joint and the challenge of treating the clinically typical "Red Knee"—patients with joint inflammation or other comorbidities which exclude them from most biologic repair options. In this portion, a porcine model of chronic OA was first established using an enhanced medial meniscus destabilization procedure in the stifle joint of the Yucatan minipig. Next, using the Yucatan minipig, an osteochondral autograft transfer (OATs) procedure was performed on the weightbearing surface of the medial femoral condyle, both with and without an adjuvant anti-inflammatory therapeutic. Data from these studies show that intraarticular anti-inflammatory therapy using interleukin-1 receptor antagonist (IL-1ra) significantly improved repair outcomes, suggesting a pathway to broaden the applicability of biologic joint restoration. This work advances our understanding of joint degeneration and repair and lays the foundation for expanding regenerative therapies to more patients with complex joint disease.